The project, led by Ian Lipkin, will explore the role of infection and immunity in ME/CFS. Many patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) report a prodrome consistent with infection and/or inflammation. Up to 40% of patients are reported to respond to intravenous infusions of the Toll-like receptor 3 agonist, Ampligen, a double-stranded RNA analogue proposed to inhibit viral replication. Others report responses to antiviral drugs specific for herpesviruses, pre- and probiotics or fecal transplantation, or monoclonal antibodies that deplete B cells. This project will use sequence-based methods for detection and characterization of bacteria, viruses, and fungi, using blood, oral, and fecal samples from ME/CFS cases and controls. We hypothesize that at least some ME/CFS patients have an infectious trigger for their disease, and that failures to implicate infectious agents reflect inadequate sampling and/or inappropriate assays. This project has the potential to lead to the development of animal models based and to identify patients with ME/CFS who may benefit from antiviral, antibiotic, or probiotic interventions.